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Source: Butterfly College Congenital Hypothyroidism (CH) is a common pediatric endocrine disease
.
If the child is not treated in time after birth, it will lead to growth retardation and mental retardation, which will cause a serious burden to the family and society
.
At the 14th Merck China Forum, Professor Gong Chunxiu from the Department of Endocrinology, Genetics and Metabolism, Beijing Children's Hospital, Capital Medical University, gave a wonderful sharing on the "Guidelines for Diagnosis and Treatment of Hypothyroidism and Genetics Progress"
.
CH is defined as abnormal function of the hypothalamus-pituitary-gonad axis (HPG axis) at birth, leading to insufficient thyroid hormone production (severe or moderate deficiency)
.
CH can be caused by dysplasia or dysfunction of the thyroid gland, as well as problems with the hypothalamus or pituitary gland
.
Currently, the incidence of CH varies from country to country
.
According to statistics, the incidence of Asian Indian babies is about 1 in 1,200, Asian (Chinese and Vietnamese) babies are about 1/2380, Hispanic babies are about 1 in 1,600, and non-Hispanic white babies are about 1 in 1200.
1/3533, and the number of non-Hispanic black babies is about 1/11,000
.
And the incidence of hypothyroidism of different etiologies is also inconsistent (see Table 1)
.
In addition, the results of the newborn screening program indicate that the incidence of congenital primary hypothyroidism seems to be increasing, which may be due to the reduction of the threshold of thyroid-stimulating hormone (TSH) for screening and the in situ thyroid (GIS) Found out
.
Table 1 The incidence of hypothyroidism of different etiologies.
In March 2021, the American Endocrinology Association-European Reference Network (ENDO-ERN) issued an updated guideline on the screening, diagnosis and treatment of CH (hereinafter referred to as the "Guide").
The guidelines are an update of the expert consensus published in 2014 and have been endorsed by the European Society of Pediatric Endocrinology (ESPE) and the European Society of Endocrinology (ESE)
.
The guidelines use the GRADE system's recommendation strength to grade (strong recommendation and weak recommendation), and grade the evidence according to the quality from high to low
.
The guidelines mainly make recommendations from the following aspects: newborn screening, principles of diagnosis and treatment, treatment and monitoring, results of screening and early treatment, and genetic counseling
.
Professor Gong gave a very detailed explanation on the update points of these five aspects
.
Neonatal screening for CH is one of the most common (treatable) causes of intellectual disability.
Delays in the diagnosis and treatment of this disease can lead to impaired neurocognitive function, even if the baby is diagnosed, if there is no treatment within 2-3 years after birth With good treatment, IQ and neurological development may be impaired, so early diagnosis and treatment are very important
.
The latest guidelines support CH screening of newborns worldwide to optimize the detection, diagnosis, treatment and follow-up of children
.
The guidelines mention that newborn screening can detect varying degrees of hypothyroidism
.
Currently, the most sensitive method for detecting primary CH is to measure TSH
.
Increasing free thyroxine (FT4) for combined testing can screen for central CH
.
In addition, special attention should be paid to the screening of special populations
.
For example, premature birth, low weight, combined with other diseases, or twin babies are prone to false negatives.
It is recommended to collect samples again after 10-14 days for screening; children with 21-trisomy syndrome are recommended to measure TSH at the end of the neonatal period
.
For primary or central CH with family history, if hypothyroidism is suspected clinically, even if TSH is normal, further evaluation is required
.
Principles of diagnosis and treatment For newly diagnosed children with CH, the guidelines strongly recommend starting levothyroxine (L-T4) therapy as soon as possible before imaging examinations
.
Imaging examination can help clarify the cause of CH.
The guidelines recommend the use of imaging B-ultrasound or thyroid scan scintillation release test or both.
In addition, knee X-ray examination can also evaluate the degree of hypothyroidism in the uterus
.
Professor Gong emphasized that in the process of imaging examination, special attention should be paid to the abnormal morphology of neonates with high TSH, and the possibility of syndromes, especially the presence or absence of cardiac malformations
.
CH treatment and monitoring Professor Gong first briefly described some of the principles related to CH treatment and monitoring in the guidelines, as shown in Figure 1
.
Figure 1 Principles related to CH treatment and monitoring.
Subsequently, Professor Gong introduced the treatment measures and monitoring frequency of primary CH and central CH in the guidelines
.
The diagnosis of primary CH should be started as soon as possible
.
Due to the large variation spectrum of hypothyroidism, the recommended dose of L-T4 can be up to 15 ug/kg
.
For severe hypothyroidism, FT4 should be below 5pmol/L, and the dose of L-T4 should be 10-15 ug/kg; for mild CH, FT4>10pmol/L, L-T4 should start with a small dose (5ug/kg)
.
Children with primary CH should start to monitor the efficacy within 1-2 weeks of starting the medication, and then monitor every two weeks until the TSH concentration is normal; after that, the frequency can be reduced to once every 1 to 3 months until the fetus is 12 months old; 12 Children from months to 3 years old can be monitored every 2-4 months, and every 3-6 months after the growth and development of the child is completed
.
For severe forms of central CH (FT4<5 pmol/L), the starting dose is 10-15ug/kg, and for mild central CH, the starting dose is 5-10ug/kg
.
In addition, for neonates with central CH, it is recommended to monitor the efficacy by measuring FT4 and TSH, which is similar to that of primary CH
.
Professor Gong also emphasized the precautions for taking L-T4 in the guide: it can be taken with milk or with meals, but avoid beans and high fiber; take it at the same time every day; compliance is very important, and attention should be paid to other diseases such as gastrointestinal diseases The resulting laboratory error
.
Results of newborn screening and early treatment The results of CH children with neonatal screening and early treatment need to be continuously evaluated
.
The guidelines recommend focusing on the assessment of neonatal nervous system development, thyroid morphology, growth, puberty and fertility, as well as bone, metabolic and cardiovascular diseases, consulting other health professionals if necessary, and providing children and families with education about congenital hypothyroidism (Picture 2)
.
Figure 2 Evaluation of children with CH.
Genetic counseling.
Abnormal expression of thyroid transcription factors can affect thyroid development and lead to abnormal thyroid function
.
Abnormal expression of transcription factors affects thyroid function differently sooner or later
.
As shown in Figure 3, the key genes that control the development of the thyroid include PAX8, NKX2-1, FOXE1, NKX2-5 and so on
.
Figure 3 The expression of thyroid transcription factors and the stages of thyroid development.
In addition, thyroid transcription factors are also closely related to other systems (Figure 4)
.
For example, FOXE1 mutation often leads to Bamforth-Lazarus syndrome, which is mainly manifested as CH, cleft lip and palate, etc.
; NKX2-1 mutation can lead to brain-pulmonary-thyroid syndrome, which mainly manifests as CH and neonatal respiratory distress syndrome
.
Figure 4 The relationship between the expression of thyroid transcription factors and other systems.
Therefore, when the thyroid function is found to be underactive and thyroid dysplasia is ruled out, attention should also be paid to whether there are other system diseases
.
When other system diseases are abnormal (such as congenital heart disease, cleft palate, hair abnormality, posterior nostril atresia, etc.
), attention should be paid to finding the cause of hypothyroidism and timely genetic testing
.
Professor Gong once again emphasized that understanding the genes related to thyroid hypoplasia, thyroid hormone synthesis disorder, TSH resistance, and central hypothyroidism is essential for the diagnosis and treatment of newborns and genetic counseling for the next pregnancy
.
Figure 5 Hypothyroidism-related genes Finally, Professor Gong concluded: The updated recommendations on the consensus guidelines on CH are applicable to global newborn screening and diagnosis, including genetics
.
Congenital hypothyroidism caused by different gene mutations is inherited in different ways, and the disease-causing genes need to be clarified to provide patients with correct genetic counseling
.
In addition, the timing of medication, dose adjustment, and withdrawal time for children are particularly critical.
The relevant treatment and monitoring principles in the guidelines should be followed to further optimize the patient's prognosis
.
.
If the child is not treated in time after birth, it will lead to growth retardation and mental retardation, which will cause a serious burden to the family and society
.
At the 14th Merck China Forum, Professor Gong Chunxiu from the Department of Endocrinology, Genetics and Metabolism, Beijing Children's Hospital, Capital Medical University, gave a wonderful sharing on the "Guidelines for Diagnosis and Treatment of Hypothyroidism and Genetics Progress"
.
CH is defined as abnormal function of the hypothalamus-pituitary-gonad axis (HPG axis) at birth, leading to insufficient thyroid hormone production (severe or moderate deficiency)
.
CH can be caused by dysplasia or dysfunction of the thyroid gland, as well as problems with the hypothalamus or pituitary gland
.
Currently, the incidence of CH varies from country to country
.
According to statistics, the incidence of Asian Indian babies is about 1 in 1,200, Asian (Chinese and Vietnamese) babies are about 1/2380, Hispanic babies are about 1 in 1,600, and non-Hispanic white babies are about 1 in 1200.
1/3533, and the number of non-Hispanic black babies is about 1/11,000
.
And the incidence of hypothyroidism of different etiologies is also inconsistent (see Table 1)
.
In addition, the results of the newborn screening program indicate that the incidence of congenital primary hypothyroidism seems to be increasing, which may be due to the reduction of the threshold of thyroid-stimulating hormone (TSH) for screening and the in situ thyroid (GIS) Found out
.
Table 1 The incidence of hypothyroidism of different etiologies.
In March 2021, the American Endocrinology Association-European Reference Network (ENDO-ERN) issued an updated guideline on the screening, diagnosis and treatment of CH (hereinafter referred to as the "Guide").
The guidelines are an update of the expert consensus published in 2014 and have been endorsed by the European Society of Pediatric Endocrinology (ESPE) and the European Society of Endocrinology (ESE)
.
The guidelines use the GRADE system's recommendation strength to grade (strong recommendation and weak recommendation), and grade the evidence according to the quality from high to low
.
The guidelines mainly make recommendations from the following aspects: newborn screening, principles of diagnosis and treatment, treatment and monitoring, results of screening and early treatment, and genetic counseling
.
Professor Gong gave a very detailed explanation on the update points of these five aspects
.
Neonatal screening for CH is one of the most common (treatable) causes of intellectual disability.
Delays in the diagnosis and treatment of this disease can lead to impaired neurocognitive function, even if the baby is diagnosed, if there is no treatment within 2-3 years after birth With good treatment, IQ and neurological development may be impaired, so early diagnosis and treatment are very important
.
The latest guidelines support CH screening of newborns worldwide to optimize the detection, diagnosis, treatment and follow-up of children
.
The guidelines mention that newborn screening can detect varying degrees of hypothyroidism
.
Currently, the most sensitive method for detecting primary CH is to measure TSH
.
Increasing free thyroxine (FT4) for combined testing can screen for central CH
.
In addition, special attention should be paid to the screening of special populations
.
For example, premature birth, low weight, combined with other diseases, or twin babies are prone to false negatives.
It is recommended to collect samples again after 10-14 days for screening; children with 21-trisomy syndrome are recommended to measure TSH at the end of the neonatal period
.
For primary or central CH with family history, if hypothyroidism is suspected clinically, even if TSH is normal, further evaluation is required
.
Principles of diagnosis and treatment For newly diagnosed children with CH, the guidelines strongly recommend starting levothyroxine (L-T4) therapy as soon as possible before imaging examinations
.
Imaging examination can help clarify the cause of CH.
The guidelines recommend the use of imaging B-ultrasound or thyroid scan scintillation release test or both.
In addition, knee X-ray examination can also evaluate the degree of hypothyroidism in the uterus
.
Professor Gong emphasized that in the process of imaging examination, special attention should be paid to the abnormal morphology of neonates with high TSH, and the possibility of syndromes, especially the presence or absence of cardiac malformations
.
CH treatment and monitoring Professor Gong first briefly described some of the principles related to CH treatment and monitoring in the guidelines, as shown in Figure 1
.
Figure 1 Principles related to CH treatment and monitoring.
Subsequently, Professor Gong introduced the treatment measures and monitoring frequency of primary CH and central CH in the guidelines
.
The diagnosis of primary CH should be started as soon as possible
.
Due to the large variation spectrum of hypothyroidism, the recommended dose of L-T4 can be up to 15 ug/kg
.
For severe hypothyroidism, FT4 should be below 5pmol/L, and the dose of L-T4 should be 10-15 ug/kg; for mild CH, FT4>10pmol/L, L-T4 should start with a small dose (5ug/kg)
.
Children with primary CH should start to monitor the efficacy within 1-2 weeks of starting the medication, and then monitor every two weeks until the TSH concentration is normal; after that, the frequency can be reduced to once every 1 to 3 months until the fetus is 12 months old; 12 Children from months to 3 years old can be monitored every 2-4 months, and every 3-6 months after the growth and development of the child is completed
.
For severe forms of central CH (FT4<5 pmol/L), the starting dose is 10-15ug/kg, and for mild central CH, the starting dose is 5-10ug/kg
.
In addition, for neonates with central CH, it is recommended to monitor the efficacy by measuring FT4 and TSH, which is similar to that of primary CH
.
Professor Gong also emphasized the precautions for taking L-T4 in the guide: it can be taken with milk or with meals, but avoid beans and high fiber; take it at the same time every day; compliance is very important, and attention should be paid to other diseases such as gastrointestinal diseases The resulting laboratory error
.
Results of newborn screening and early treatment The results of CH children with neonatal screening and early treatment need to be continuously evaluated
.
The guidelines recommend focusing on the assessment of neonatal nervous system development, thyroid morphology, growth, puberty and fertility, as well as bone, metabolic and cardiovascular diseases, consulting other health professionals if necessary, and providing children and families with education about congenital hypothyroidism (Picture 2)
.
Figure 2 Evaluation of children with CH.
Genetic counseling.
Abnormal expression of thyroid transcription factors can affect thyroid development and lead to abnormal thyroid function
.
Abnormal expression of transcription factors affects thyroid function differently sooner or later
.
As shown in Figure 3, the key genes that control the development of the thyroid include PAX8, NKX2-1, FOXE1, NKX2-5 and so on
.
Figure 3 The expression of thyroid transcription factors and the stages of thyroid development.
In addition, thyroid transcription factors are also closely related to other systems (Figure 4)
.
For example, FOXE1 mutation often leads to Bamforth-Lazarus syndrome, which is mainly manifested as CH, cleft lip and palate, etc.
; NKX2-1 mutation can lead to brain-pulmonary-thyroid syndrome, which mainly manifests as CH and neonatal respiratory distress syndrome
.
Figure 4 The relationship between the expression of thyroid transcription factors and other systems.
Therefore, when the thyroid function is found to be underactive and thyroid dysplasia is ruled out, attention should also be paid to whether there are other system diseases
.
When other system diseases are abnormal (such as congenital heart disease, cleft palate, hair abnormality, posterior nostril atresia, etc.
), attention should be paid to finding the cause of hypothyroidism and timely genetic testing
.
Professor Gong once again emphasized that understanding the genes related to thyroid hypoplasia, thyroid hormone synthesis disorder, TSH resistance, and central hypothyroidism is essential for the diagnosis and treatment of newborns and genetic counseling for the next pregnancy
.
Figure 5 Hypothyroidism-related genes Finally, Professor Gong concluded: The updated recommendations on the consensus guidelines on CH are applicable to global newborn screening and diagnosis, including genetics
.
Congenital hypothyroidism caused by different gene mutations is inherited in different ways, and the disease-causing genes need to be clarified to provide patients with correct genetic counseling
.
In addition, the timing of medication, dose adjustment, and withdrawal time for children are particularly critical.
The relevant treatment and monitoring principles in the guidelines should be followed to further optimize the patient's prognosis
.
